PMID- 17181160
OWN - NLM
STAT- MEDLINE
DCOM- 20070202
LR  - 20191210
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 49
IP  - 26
DP  - 2006 Dec 28
TI  - Design, synthesis, and biological evaluation of peptidomimetic inhibitors of 
      factor XIa as novel anticoagulants.
PG  - 7781-91
AB  - Human coagulation factor XIa (FXIa), a serine protease activated by site-specific 
      cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme 
      in the amplification phase of the coagulation cascade. To investigate the 
      potential of FXIa inhibitors as safe anticoagulants, a series of potent, 
      selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some 
      of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold 
      FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of 
      these inhibitors, 36, demonstrates its unique binding interactions with FXIa. 
      Compound 32 caused a doubling of the activated partial thromboplastin time in 
      human plasma at 2.4 microM and was efficacious in a rat model of venous 
      thrombosis. These data suggest that factor XIa plays a significant role in venous 
      thrombosis and may be a suitable target for the development of antithrombotic 
      therapy.
FAU - Lin, Jian
AU  - Lin J
AD  - Daiichi Asubio Medical Research Laboratories LLC (DAIAMED), One Kendall Square 
      Building 700, Cambridge, MA 02139, USA. jlin@epixpharma.com
FAU - Deng, Hongfeng
AU  - Deng H
FAU - Jin, Lei
AU  - Jin L
FAU - Pandey, Pramod
AU  - Pandey P
FAU - Quinn, Jesse
AU  - Quinn J
FAU - Cantin, Susan
AU  - Cantin S
FAU - Rynkiewicz, Michael J
AU  - Rynkiewicz MJ
FAU - Gorga, Joan C
AU  - Gorga JC
FAU - Bibbins, Frank
AU  - Bibbins F
FAU - Celatka, Cassandra A
AU  - Celatka CA
FAU - Nagafuji, Pamela
AU  - Nagafuji P
FAU - Bannister, Thomas D
AU  - Bannister TD
FAU - Meyers, Harold V
AU  - Meyers HV
FAU - Babine, Robert E
AU  - Babine RE
FAU - Hayward, Neil J
AU  - Hayward NJ
FAU - Weaver, David
AU  - Weaver D
FAU - Benjamin, Howard
AU  - Benjamin H
FAU - Stassen, Frans
AU  - Stassen F
FAU - Abdel-Meguid, Sherin S
AU  - Abdel-Meguid SS
FAU - Strickler, James E
AU  - Strickler JE
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anticoagulants)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Peptide Fragments)
RN  - 0 (Serine Proteinase Inhibitors)
RN  - EC 3.4.21.27 (Factor XIa)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Animals
MH  - Anticoagulants/chemical synthesis/chemistry/*pharmacology
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - *Drug Design
MH  - Factor XIa/*antagonists & inhibitors
MH  - *Factor Xa Inhibitors
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Male
MH  - Molecular Structure
MH  - Partial Thromboplastin Time
MH  - Peptide Fragments/*chemical synthesis/chemistry/pharmacology
MH  - Protein Binding
MH  - Protein Conformation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Serine Proteinase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - Thrombin/antagonists & inhibitors
MH  - Venous Thrombosis/drug therapy
EDAT- 2006/12/22 09:00
MHDA- 2007/02/03 09:00
CRDT- 2006/12/22 09:00
PHST- 2006/12/22 09:00 [pubmed]
PHST- 2007/02/03 09:00 [medline]
PHST- 2006/12/22 09:00 [entrez]
AID - 10.1021/jm060978s [doi]
PST - ppublish
SO  - J Med Chem. 2006 Dec 28;49(26):7781-91. doi: 10.1021/jm060978s.